850628-98-7Relevant academic research and scientific papers
Radiosynthesis and radiopharmacological evaluation of cyclin-dependent kinase 4 (Cdk4) inhibitors
Koehler, Lena,Graf, Franziska,Bergmann, Ralf,Steinbach, J?rg,Pietzsch, Jens,Wuest, Frank
experimental part, p. 727 - 737 (2010/04/04)
Tumor cells are characterized by their loss of growth control resulting from alterations in regulating pathways of the cell cycle, such as a deregulated cyclin-dependent kinase (Cdk) activity and/or Cdk expression. Appropriately radiolabeled Cdk4 inhibitors are discussed as promising molecular probes for imaging cell proliferation processes and tumor visualization by PET. This work describes the design, synthesis and radiopharmacological evaluation of two 124I-labeled Cdk4 inhibitors as potential radiotracers for imaging of Cdk4 in vivo. Treatment of a solution containing labeling precursors with [124I]NaI gave radiolabeled Cdk4 inhibitors [124I]CKIA and [124I]CKIB in radiochemical yields of up to 35%. 124I-labeled radiotracers [124I]CKIA and [124I]CKIB were used in cell uptake studies as well as biodistribution studies in Wistar rats and small-animal PET in tumor-bearing mice. In vitro radiotracer uptake studies in adherent tumor cells using [124I]CKIA showed substantial uptake in HT-29 and FaDu cells (750-850 %ID/mg?protein [124I]CKIA and 900-1000?%ID/mg protein [124I]CKIB) after 1?h at 37?°C. Biodistribution of [124I]CKIA and [124I]CKIB showed rapid blood clearance of radioactivity and an accumulation as well as metabolization in the liver. Both radiotracers were administered intravenously to mouse FaDu xenograft tumor model and imaging studies were performed on a small-animal PET scanner. Both imaging techniques showed only little uptake of both radiotracers in the FaDu tumor xenografts.
Pyrido[2,3-d]pyrimidin-7-ones as specific inhibitors of cyclin-dependent kinase 4
VanderWel, Scott N.,Harvey, Patricia J.,McNamara, Dennis J.,Repine, Joseph T.,Keller, Paul R.,Quin III, John,Booth, R. John,Elliott, William L.,Dobrusin, Ellen M.,Fry, David W.,Toogood, Peter L.
, p. 2371 - 2387 (2007/10/03)
Inhibition of the cell cycle kinase, cyclin-dependent kinase-4 (Cdk4), is expected to provide an effective method for the treatment of proliferative diseases such as cancer. The pyrido[2,3-d]-pyrimidin-7-one template has been identified previously as a privileged structure for the inhibition of ATP-dependent kinases, and good potency against Cdks has been reported for representative examples. Obtaining selectivity for individual Cdk enzymes, particularly Cdk4, has been challenging. Here, we report that the introduction of a methyl substituent at the C-5 position of the pyrido[2,3-d]pvrimidin-7-one template is sufficient to confer excellent selectivity for Cdk4 vs other Cdks and representative tyrosine kinases. Further optimization led to the identification of highly potent and selective inhibitors of Cdk4 that exhibit potent antiproliferative activity against human tumor cells in vitro. The most selective Cdk4 inhibitors were evaluated for antitumor activity against MDA-MB-435 human breast carcinoma xenografts in mice.
